The relations between the chemical structure of non-electrolytes and their ability to permeate cell membranes are analysed at the level of molecular forces, using the measurements of reflexion coefficients in gall-bladder epithelial cells tabulated in the preceding paper. Stronger solute:water forces and weaker solute:membrane forces are associated with lower permeating power. The portions of the membrane controlling non-electrolyte permeation behave as nearly pure hydrocarbons with very few hydrogen-bonding sites. Most substituents (hydroxyl, ether, carbonyl, ester, amino, amide, urea, nitrile) are shown to decrease permeation in proportion to the number and strength of intermolecular hydrogen bonds which they form with water, while intramolecular hydrogen bonding accelerates permeation. Carbon-carbon double bonds and triple bonds and aromatic residues decrease permeability due to hydrogen bonds involving π electrons. Inductive effects, in which a substituent indirectly modifies permeability by withdrawing or releasing electrons at an adjacent hydrogen bonding site, are most noticeable for halogens, the nitro group, double and triple bonds, and branched alkyl groups. Altered forces between membrane hydrocarbons and the solute retard the permeation (weaker forces) of fluorine compounds and branched compounds, and slightly accelerate the permeation (stronger forces) of other halogen derivatives and compounds with long carbon chains. The main factor in the increase of permeability with increasing hydrocarbon chain length is an entropy effect associated with a change in local water structure; and this effect is partly responsible for the decrease in permeability with chain branching, whose origin is particularly complex.
Intramolecular Hydrogen Bonding 2021
